NCT06758401From ClinicalTrials.govRecruiting

This is a Study to Learn About How the Combination of the Study Medicines Sigvotatug Vedotin Plus Pembrolizumab Works in People With Non-small Cell Lung Cancer With High Levels of PD-L1.

AN OPEN-LABEL, RANDOMIZED, CONTROLLED PHASE 3 STUDY OF SIGVOTATUG VEDOTIN IN COMBINATION WITH PEMBROLIZUMAB COMPARED WITH PEMBROLIZUMAB MONOTHERAPY AS FIRST-LINE TREATMENT IN PARTICIPANTS WITH PD-L1 HIGH (≥50% OF TUMOR CELLS EXPRESSING PD-L1), LOCALLY ADVANCED, UNRESECTABLE, OR METASTATIC NON-SMALL CELL LUNG CANCER

Non-Small Cell Lung Cancer
Carcinoma, Non-Small-Cell Lung
Carcinoma, Non-Small-Cell Lung (NSCLC)

At a glance

Phase: Phase 3
Study type: Interventional
Sponsor: Pfizer
Enrolment target: 714
Started: 23 July 2025
Main results due: 5 September 2028
Study sites: 389
Registry updated: 25 September 2026

Can you take part?

Aged 18 years and over.
Open to any sex.
You need the condition being studied — healthy volunteers are not accepted.

These are the headline rules only. Every study has a longer list, and whether you are eligible is decided by the research team at the site — never by this page.

Read the full eligibility criteria

Inclusion Criteria:

1. Participants must meet the following criteria:

1. Have pathologically confirmed Stage IIIB or IIIC NSCLC and not be a candidate for surgical resection or definitive chemoradiation, or Stage IV NSCLC per the AJCC Staging Manual (Version 8.0) and the UICC Staging System (Eighth edition).
2. Participants with known AGAs including EGFR, ALK, ROS1, NTRK, BRAF, RET, and MET, for which there are approved and available first-line therapies per local SOC are ineligible. Documented negative results for EGFR, ALK, and ROS1 AGAs are required for participants with non-squamous histology.
3. Participants with large cell neuroendocrine carcinoma are excluded.
4. Must be an appropriate candidate for treatment with pembrolizumab monotherapy per local guidelines.
2. Tumor has PD-L1 expression in ≥50% of tumor cells (TPS ≥50%) as determined by local testing.
3. Measurable disease based on RECIST v1.1 per investigator.
4. Resolution of acute effects of any prior therapy to either baseline severity or NCI CTCAE Grade 1 or less (except for AEs not constituting a safety risk in the investigator's judgment), unless otherwise excluded.

Exclusion Criteria:

1. Life expectancy of \<3 months in the opinion of the investigator.
2. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or make the participant inappropriate for the study.
3. Participants with any history of another malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy.
4. Known or suspected hypersensitivity, intolerance, or contraindication to any excipient contained in the drug formulation of sigvotatug vedotin or pembrolizumab.
5. Participants with any of the following respiratory conditions:

1. Evidence of noninfectious or drug-induced ILD or pneumonitis
2. Known DLCO (adjusted for hemoglobin) \<50% predicted.
3. Grade ≥3 pulmonary disease unrelated to underlying malignancy
6. Known active CNS lesions are excluded. Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be eligible. Up to 5 clinically asymptomatic brain metastases of longest diameter \<1.0 cm are permitted without definitive surgery and/or radiotherapy.
7. Major surgery (defined as a surgery requiring inpatient hospitalization of at least 48 hours) within 21 days or minor surgery (excluding peripherally inserted central catheter placement and implantable central venous port placement) within 3 days prior to first dose of study intervention.
8. Receipt of a live vaccine within 30 days prior to first dose of study intervention.
9. Pre-existing peripheral neuropathy Grade ≥2 per NCI CTCAE v5.0.
10. Uncontrolled diabetes mellitus, defined as HbA1c ≥8.0% or HbA1c between 7.0% and 8.0% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
11. Prior immune-related AE that led to anti-PD-(L)1 treatment discontinuation, required a high-dose steroid taper (≥0.5 mg/kg prednisone or equivalent per day) for \>2 weeks, or required treatment with systemic immunosuppressive therapy.
12. History of autoimmune disease that has required systemic treatment in the past 2 years
13. Participants with prior solid organ or bone marrow transplantation.
14. Currently receiving a high-dose steroid (\>10 mg prednisone or equivalent per day) or other immune suppressant or has a condition requiring a chronic high-dose steroid or immune suppressant.
15. Prior and concomitant therapy:

1. Any prior treatment with MMAE-derived drugs or IB6 targeting agents.
2. Prior systemic therapy, including anti-PD-(L)1 therapy, for locally advanced, unresectable, or metastatic NSCLC.

* (Neo)adjuvant anti-PD-(L)1 is allowed if recurrence or progression occurred ≥9 months after the last dose.
* Other (neo)adjuvant or definitive therapy is allowed if recurrence or progression occurred ≥6 months after the last dose.
3. Prior radiotherapy to the lung within 6 months of first dose of study intervention, referencing the last date radiotherapy was received. This includes both curative and palliative radiotherapy.
4. Chemotherapy, biologics, and/or other antitumor treatment with immunotherapy not specifically prohibited that is completed less than 4 weeks prior to first dose of study intervention, or 2 weeks for palliative radiotherapy.
5. Any prior therapy with an immune-oncology agent directed to a stimulatory or co-inhibitory T-cell receptor
16. History of or current ongoing infection, including participants positive for active HIV, HBV, or HCV.
17. Severe uncontrolled cardiac or cerebrovascular condition within the previous 6 months

What this study is about

In the sponsor’s own words, from the registry.

The purpose of the study is to compare how the new combination treatment (Sigvotatug Vedotin plus pembrolizumab) works compared to pembrolizumab alone in patients with non-small cell lung cancer (NSCLC) with high levels of PD-L1. This is a protein that acts as a kind of "brake" to keep the body's immune responses under control.

The study is seeking for participants who:

* Are confirmed to have NSCLC (Stage 3 or 4). * Have PD-L1 levels in more than 50% of the cancer cells.

All participants in this study will receive pembrolizumab at the study clinic once every 6 weeks as an intravenous (IV) infusion (give directly into a vein). In addition, half of the participants will also receive Sigvotatug Vedotin once every 2 weeks as an IV infusion in addition to receiving pembrolizumab.

Participants may receive pembrolizumab for up to about two years. Those participants taking Sigvotatug Vedotin can continue until their NSCLC is no longer responding. The study team will monitorsee how each participant is doing with the study treatment during regular visits at the clinic.

Study sites(389)

Providence Medical Foundation
Fullerton, California, United States
Recruiting
Providence St. Jude Medical Center Virginia K. Crosson Cancer Center and Infusion Center
Fullerton, California, United States
Recruiting
Providence St. Jude Medical Center
Fullerton, California, United States
Recruiting
St. Jude Heritage Medical Group - Fullerton Plaza Multi-Specialty Clinic (Pulmonary Function Test)
Fullerton, California, United States
Recruiting
Intermountain Health Cancer Center Lutheran Hospital
Golden, Colorado, United States
Recruiting
Cancer Centers of Colorado St. Mary's Regional Hospital
Grand Junction, Colorado, United States
Recruiting
Intermountain Health St. Mary's Regional Hospital
Grand Junction, Colorado, United States
Recruiting
Intermountain Health
Grand Junction, Colorado, United States
Recruiting
Intermountain Health Lutheran Hospital
Wheat Ridge, Colorado, United States
Recruiting
Washington DC Veterans Affairs Medical Center
Washington D.C., District of Columbia, United States
Recruiting
Mid Florida Hematology and Oncology Center
Orange City, Florida, United States
Recruiting
BRCR Global
Plantation, Florida, United States
Recruiting
Endeavor Health
Elmhurst, Illinois, United States
Recruiting
Hope and Healing Cancer Services
Hinsdale, Illinois, United States
Recruiting
Advocate Medical Group - Libertyville Oncology
Libertyville, Illinois, United States
Recruiting
Endeavor Health
Naperville, Illinois, United States
Recruiting
Hope and Healing Cancer Services
New Lenox, Illinois, United States
Recruiting
Advocate Christ Medical Center
Oak Lawn, Illinois, United States
Recruiting
Advocate Lutheran General Hospital
Park Ridge, Illinois, United States
Recruiting
Saint Luke's South Hospital
Overland Park, Kansas, United States
Recruiting
Maine Medical Center
Portland, Maine, United States
Recruiting
MaineHealth Cancer Care and Blood Disorders Scarborough
Scarborough, Maine, United States
Recruiting
MaineHealth Cancer Care and IV Therapy - South Portland
South Portland, Maine, United States
Recruiting
Southcoast Centers for Cancer Care
Fairhaven, Massachusetts, United States
Recruiting
Southcoast Centers for Cancer Care
Fall River, Massachusetts, United States
Recruiting
Corewell Health - Butterworth Hospital
Grand Rapids, Michigan, United States
Recruiting
Corewell Health - Lemmen Holton Cancer Pavilion
Grand Rapids, Michigan, United States
Recruiting
Corewell Health - Research Specimen Processing Area
Grand Rapids, Michigan, United States
Recruiting
Corewell Health Investigational Drug Services
Grand Rapids, Michigan, United States
Recruiting
Corewell Health
Grand Rapids, Michigan, United States
Recruiting
Minnesota Oncology Hematology, PA
Burnsville, Minnesota, United States
Recruiting
Minnesota Oncology Hematology PA
Coon Rapids, Minnesota, United States
Recruiting
M Health Fairview Cancer Clinic-Edina
Edina, Minnesota, United States
Recruiting
Minnesota Oncology Hematology PA
Edina, Minnesota, United States
Recruiting
Minnesota Oncology Hematology PA
Maple Grove, Minnesota, United States
Recruiting
M Health Fairview St. John's Hospital
Maplewood, Minnesota, United States
Recruiting
Minnesota Oncology Hematology PA
Maplewood, Minnesota, United States
Recruiting
Hennepin County Medical Center
Minneapolis, Minnesota, United States
Recruiting
North Memorial Health Cancer Center
Robbinsdale, Minnesota, United States
Recruiting
Metro Minnesota Community Oncology Research Consortium (MMCORC)
Saint Louis Park, Minnesota, United States
Recruiting
Park Nicollet Frauenshuh Cancer Center
Saint Louis Park, Minnesota, United States
Recruiting
Regions Hospital
Saint Paul, Minnesota, United States
Recruiting
Minnesota Oncology Hematology, P.A. Cornerstone Medical Specialty Center
Woodbury, Minnesota, United States
Recruiting
Jackson Oncology Associates, PLLC
Jackson, Mississippi, United States
Recruiting
Jackson Oncology Associates, PLLC
Jackson, Mississippi, United States
Recruiting
Saint Luke's Hospital of Kansas City
Kansas City, Missouri, United States
Recruiting
Saint Luke's East Hospital
Lee's Summit, Missouri, United States
Recruiting
SCL Health - Montana
Billings, Montana, United States
Recruiting
SCL Health - Montana
Billings, Montana, United States
Recruiting
Oncology Hematology West, PC dba Nebraska Cancer Specialists - Fremont
Fremont, Nebraska, United States
Recruiting
Oncology Hematology West, PC dba Nebraska Cancer Specialists - Grand Island
Grand Island, Nebraska, United States
Recruiting
Oncology Hematology West, PC dba Nebraska Cancer Specialists - Regional
Grand Island, Nebraska, United States
Recruiting
Kearney Cancer Center
Kearney, Nebraska, United States
Recruiting
Cancer Partners of Nebraska
Lincoln, Nebraska, United States
Recruiting
Oncology Hematology West P.C. dba Nebraska Cancer Specialists - Methodist
Omaha, Nebraska, United States
Recruiting
Oncology Hematology West, PC dba Nebraska Cancer Specialists - Bergan
Omaha, Nebraska, United States
Recruiting
Oncology Hematology West P.C. dba Nebraska Cancer Specialists
Omaha, Nebraska, United States
Recruiting
Hematology Oncology Associates of Rockland
Nyack, New York, United States
Recruiting
Brody School of Medicine at East Carolina University
Greenville, North Carolina, United States
Recruiting
ECU Health Medical Center
Greenville, North Carolina, United States
Recruiting

Showing 60 of 389 sites — filter to narrow it down. 355 of the 389 sites on this study are recruiting right now — a site can stop enrolling while the study as a whole is still open.

Source: ClinicalTrials.gov record NCT06758401. Trialion does not run this study, is not paid to refer anyone to it, and cannot enrol you. Eligibility is always decided by the research team at the site.

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